Abstract Obesity remains one of the greatest and most modifiable risk factors associated with the development and progression of knee osteoarthritis (OA). While numerous studies hypothesize that the primary pathological stimulus is increased joint loading resulting from elevated body mass, there are limited data on the effects of obesity on local in vivo strain distributions in knee cartilage. Furthermore, recent studies suggest that both biomechanical and inflammatory factors play a role in obesity-induced OA. This is evidenced by elevated OA risk in non-weight bearing joints such as the hand and wrist. Obese subjects may exhibit changes in both articular cartilage composition and function that precede the onset of symptomatic OA. For example, changes to cartilage in early OA include proteoglycan loss and disruption of the collagen matrix, both of which can reduce cartilage modulus and thus its deformation response to load. In line with this hypothesis, our recent pilot data indicates that cartilage strains in response to activities of daily living are increased in participants with high body mass index (BMI) compared to control subjects with normal BMI. However, it is unclear whether increased cartilage strains are due to alterations in cartilage composition, increased joint loading resulting from elevated body mass, or a combination of factors. Furthermore, it is unclear whether these changes in cartilage composition and mechanical function are reversible with weight loss. Thus, our central hypothesis is that obesity alters both the composition and mechanical function of cartilage and that these changes are reversible with weight loss. To address this hypothesis, we will use a novel combination of magnetic resonance imaging (MRI) and high- speed biplanar radiography to evaluate the effects of obesity and weight loss on in vivo cartilage strains during a controlled functional activity (treadmill walking). Additionally, we will use quantitative MR imaging (T1-rho and T2 mapping) to evaluate whether obesity and weight loss alter the composition and organization of the cartilage matrix in both the knee and wrist. Furthermore, we will investigate whether alterations in cartilage composition occur in the wrist cartilage. This will establish the role of systemic factors that relate to obesity and weight loss, as the wrist is a non-weight bearing joint. Changes in cartilage composition and mechanical function will be compared to a panel of local and systemic biomarkers in order to help establish clinically applicable surrogate measures of OA progression. The data generated from the proposed research are crucial for determining whether early degenerative changes in cartilage composition and mechanical function can be reversed. Ultimately, these data are critical to identifying new targets for clinical interventions aimed at OA prevention and treatment.